Avanafil (AVA) is a novel selective phosphodiesterase type 5 (PDE5) inhibitor. AVA attained FDA approval for treating erectile dysfunction in 2012 to be the fourth marketed PDE5 inhibitor (Bruzziches et al., 2013; Huang and Lie, 2013). AVA has a molecular weight of 483.951 g/mol and two pKa values, 11.84 (acidic) and 5.89 (basic). It has a log P value of 1.84, and consequently, it suffers from low solubility in water, methanol, and ethanol (<1 mg/mL at 25° C.) (Can, 2018; Soliman et al., 2017). AVA also suffers from considerable pre-systemic metabolism and altered absorption in the presence of food despite its rapid absorption upon oral administration. The aforementioned drawbacks result in limited oral bioavailability (Burke and Evans, 2012; European Medicines Agency, 2013; Fahmy et al., 2014; Katz et al., 2014).
Transdermal delivery represents a promising approach for the delivery of drugs undergoing first pass metabolism. It has the advantages of surmounting the first pass effect of the drugs compared to the conventional oral route and increasing patient compliance via convenient and painless administration compared to other invasive routes. In addition, it could provide controlled drug delivery and reduced side effects (Ahad et al., 2014; Alkilani et al., 2015; Lakshmi et al., 2013). However, the main obstacle for transdermal delivery is the reduced permeation of drugs owing to the natural barrier property of the outermost epidermal layer (stratum corneum). To circumvent this barrier, several approaches have been investigated including drug manipulation, modification of the stratum corneum through iontophoresis, and the utilization of chemical penetration enhancers and nanocarriers (Dragicevic et al., 2016). Lipid vesicular systems have been widely investigated for drug delivery via dermal and transdermal routes (Ashtikar et al., 2016). They could effectively enhance cutaneous drug accumulation; however, several studies demonstrated they had only limited ability to deliver the drug effectively across the skin (Mura et al., 2009; Romero and Morilla, 2013). Accordingly, the researchers directed their focus towards the development of new generations of flexible lipid vesicular systems including transferosomes, ethosomes, and more recently, invasomes (Badr-Eldin and Ahmed, 2016; Mahmood et al., 2018; Shah et al., 2015).
Invasomes are innovative elastic vesicles comprising phosphatidylcholine, ethanol, and terpene(s). They exhibit improved cutaneous and percutaneous absorption of aqueous and lipid soluble drugs compared to conventional liposomes (Dragicevic-Curic et al., 2008; Dwivedi et al., 2017). Terpenes could potentially enhance drug penetration through disrupting the tight lipid packing of the epidermal layer (stratum corneum) and interacting with intracellular proteins (Aqil et al., 2007; Yang et al., 2013). Ethanol enhances the penetration through the stratum corneum. Moreover, it supplies a net negative surface charge and protects against vesicle aggregation owing to electrostatic repulsion (El-Nabarawi et al., 2018; Paolino et al., 2005).
Several researchers have investigated invasomes as potential delivery systems for enhancing transdermal penetration of drugs. Ntimenou el al. (Ntimenou et al., 2012) reported the superiority of invasomes to enhance the skin permeation ability of drug molecules compared to other lipid vesicular systems. Minimal skin permeation of the model drug (calcein) was observed from aqueous solution, whereas the drug permeation was slightly enhanced from conventional liposomes and enhanced by 1.8 and 7.2 fold from transfersomes and invasomes, respectively.